| Literature DB >> 27773628 |
Jacob E Choby1, Laura A Mike2, Ameya A Mashruwala3, Brendan F Dutter4, Paul M Dunman5, Gary A Sulikowski4, Jeffrey M Boyd6, Eric P Skaar7.
Abstract
The rising problem of antimicrobial resistance in Staphylococcus aureus necessitates the discovery of novel therapeutic targets for small-molecule intervention. A major obstacle of drug discovery is identifying the target of molecules selected from high-throughput phenotypic assays. Here, we show that the toxicity of a small molecule termed '882 is dependent on the constitutive activity of the S. aureus virulence regulator SaeRS, uncovering a link between virulence factor production and energy generation. A series of genetic, physiological, and biochemical analyses reveal that '882 inhibits iron-sulfur (Fe-S) cluster assembly most likely through inhibition of the Suf complex, which synthesizes Fe-S clusters. In support of this, '882 supplementation results in decreased activity of the Fe-S cluster-dependent enzyme aconitase. Further information regarding the effects of '882 has deepened our understanding of virulence regulation and demonstrates the potential for small-molecule modulation of Fe-S cluster assembly in S. aureus and other pathogens.Entities:
Keywords: SaeRS; Staphylococcus; aconitase; fermentation; iron-sulfur cluster; virulence factors
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Year: 2016 PMID： 27773628 PMCID： PMC5117899 DOI： 10.1016/j.chembiol.2016.09.012
Source DB: PubMed Journal: Cell Chem Biol ISSN： 2451-9448 Impact factor: 8.116